Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, typically develops on the background of chronic liver disease and is an aggressive disease with dismal prognosis. Studies ...using next-generation sequencing of multiple regions of the same tumour nodule suggest different patterns of HCC evolution and confirm the high molecular heterogeneity in a subset of patients. Different hypotheses have been proposed to explain tumour evolution, including clonal selection or neutral and punctuated acquisition of genetic alterations. In parallel, data indicate a fundamental contribution of nonmalignant cells of the tumour microenvironment to cancer clonal evolution. Delineating these dynamics is crucial to improve the treatment of patients with HCC, and particularly to help understand how HCC evolution drives resistance to systemic therapies. A number of new minimally invasive techniques, such as liquid biopsies, could help track cancer evolution in HCC. These tools might improve our understanding of how systemic therapies affect tumour clonal composition and could facilitate implementation of real-time molecular monitoring of patients with HCC.
Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality worldwide. Around half of patients with HCC will receive systemic therapies during their life span. The pivotal positive ...sorafenib trial and regulatory approval in 2007 was followed by a decade of negative studies with drugs leading to marginal antitumoral efficacy, toxicity, or trials with a lack of enrichment strategies. This trend has changed over the last 2 years with several compounds, such as lenvatinib (in first-line) and regorafenib, cabozantinib, ramucirumab and nivolumab (in second-line), showing clinical benefit. These successes came at a cost of increasing the complexity of decision-making, and ultimately, impacting the design of future clinical trials. Nowadays, life expectancy with single active agents has surpassed the threshold of 1 year and sequential strategies have provided encouraging outcomes. Overall survival (OS) remains the main endpoint in phase III investigations, but as in other solid tumours, there is a clear need to define surrogate endpoints that both reliably recapitulate survival benefits and can be assessed before additional efficacious drugs are administered. A thorough analysis of 21 phase III trials published in advanced HCC demonstrated a moderate correlation between progression-free survival (PFS) or time to progression (TTP) and OS (R = 0.84 and R = 0.83, respectively). Nonetheless, the significant differences in PFS identified in 7 phase III studies only correlated with differences in OS in 3 cases. In these cases, the hazard ratio (HR) for PFS was ≤0.6. Thus, this threshold is herein proposed as a potential surrogate endpoint of OS in advanced HCC. Conversely, PFS with an HR between 0.6–0.7, despite significance, was not associated with better survival, and thus these magnitudes are considered uncertain surrogates. In the current review, we discuss the reasons for positive or negative phase III trials in advanced HCC, and the strengths and limitations of surrogate endpoints (PFS, TTP and objective response rate ORR) to predict survival.
Hepatocellular carcinoma (HCC) has emerged as a major cause of cancer-related death. Its mortality has increased in Western populations, with a minority of patients diagnosed at early stages, when ...curative treatments are feasible. Only the multikinase inhibitor sorafenib is available for the management of advanced cases. During the last 10 years, there has been a clear delineation of the landscape of genetic alterations in HCC, including high-level DNA amplifications in chromosome 6p21 ( VEGFA ) and 11q13 ( FGF19/CNND1 ), as well as homozygous deletions in chromosome 9 ( CDKN2A ). The most frequent mutations affect TERT promoter (60%), associated with an increased telomerase expression. TERT promoter can also be affected by copy number variations and hepatitis B DNA insertions, and it can be found mutated in preneoplastic lesions. TP53 and CTNNB1 are the next most prevalent mutations, affecting 25%−30% of HCC patients, that, in addition to low-frequency mutated genes (eg, AXIN1, ARID2, ARID1A, TSC1/TSC2, RPS6KA3, KEAP1, MLL2), help define some of the core deregulated pathways in HCC. Conceptually, some of these changes behave as prototypic oncogenic addiction loops, being ideal biomarkers for specific therapeutic approaches. Data from genomic profiling enabled a proposal of HCC in 2 major molecular clusters (proliferation and nonproliferation), with differential enrichment in prognostic signatures, pathway activation and tumor phenotype. Translation of these discoveries into specific therapeutic decisions is an unmeet medical need in this field.
Summary The high failure rate of phase 3 trials in oncology is forcing the scientific community to rethink drug development strategies and optimize trial design. The current paradigm of systemic ...therapies is progressively favoring molecular-based patient selection. In hepatocellular carcinoma, four out of the five phase 3 trials that tested molecular therapies in the last 5 years have been negative. None of them included enriched populations using predicted biomarkers of response. Hence, there is an increasing need to provide new targets and refine selection criteria in HCC clinical trials using molecular readouts of tumor biology.
Summary Hepatocellular carcinoma (HCC) is a highly heterogeneous disease, both clinically and from a molecular standpoint. The advent of next-generation sequencing technologies has provided new ...opportunities to extensively analyze molecular defects in HCC samples. This has uncovered major cancer driver genes and associated oncogenic pathways operating in HCC. More sophisticated analyses of sequencing data has linked specific nucleotide patterns to external toxic agents and defined so-called ‘mutational signatures’ in HCC. Molecular signatures, taking into account intra- and inter-tumor heterogeneity, and their functional validation could provide useful data to predict treatment response to molecular therapies. In this review we will focus on the current knowledge of deep sequencing in HCC and its foreseeable clinical impact.
Abstract Primary liver cancer is the second leading cause of cancer-related death worldwide and therefore a major public health challenge. We review hypotheses of the cell of origin of liver ...tumorigenesis, and clarify the classes of liver cancer, based on molecular features and how these affect patient prognosis. Primary liver cancer comprises hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA), and other rare tumors, notably fibrolamellar carcinoma and hepatoblastoma. The molecular and clinical features of HCC vs iCCA are distinct, although they have overlapping risk factors and pathways of oncogenesis. A better understanding of the cell types originating liver cancer can aid in exploring molecular mechanisms of carcinogenesis and therapeutic options. Molecular studies have identified adult hepatocytes as the cell of origin. These cells have been proposed to transform directly into HCC cells (via a sequence of genetic alterations), to de-differentiate into hepatocyte precursor cells (which then become HCC cells that express progenitor cell markers), or to trans-differentiate into biliary-like cells (which give rise to iCCA). Alternatively, progenitor cells also give rise to HCCs and iCCAs with markers of progenitor cells. Advances in genome profiling and next-generation sequencing have led to the classification of HCCs based on molecular features, and assigned them to categories such as proliferation–progenitor, proliferation–transforming growth factor beta, and Wnt–catenin beta 1. iCCAs have been assigned to categories of proliferation and inflammation. Overall, proliferation subclasses are associated with a more aggressive phenotype and poor outcome of patients, although more specific signatures have refined our prognostic abilities. Analyses of genetic alterations have identified those that might be targeted therapeutically, such as fusions in the FGFR2 gene and mutations in genes encoding isocitrate dehydrogenases (in approximately 60% of iCCAs) or amplifications at 11q13 and 6p21 (in approximately 30% of HCCs). Further studies of these alterations are needed before these can be used as biomarkers in clinical decision making.
Clonal evolution of a tumor ecosystem depends on different selection pressures that are principally immune and treatment mediated. We integrate RNA-seq, DNA sequencing, TCR-seq and SNP array data ...across multiple regions of liver cancer specimens to map spatio-temporal interactions between cancer and immune cells. We investigate how these interactions reflect intra-tumor heterogeneity (ITH) by correlating regional neo-epitope and viral antigen burden with the regional adaptive immune response. Regional expression of passenger mutations dominantly recruits adaptive responses as opposed to hepatitis B virus and cancer-testis antigens. We detect different clonal expansion of the adaptive immune system in distant regions of the same tumor. An ITH-based gene signature improves single-biopsy patient survival predictions and an expression survey of 38,553 single cells across 7 regions of 2 patients further reveals heterogeneity in liver cancer. These data quantify transcriptomic ITH and how the different components of the HCC ecosystem interact during cancer evolution.
Mortality owing to liver cancer has increased in the past 20 years, and the latest estimates indicate that the global health burden of this disease will continue to grow. Most patients with ...hepatocellular carcinoma (HCC) are still diagnosed at intermediate or advanced disease stages, where curative approaches are often not feasible. Among the treatment options available, the molecular targeted agent sorafenib is able to significantly increase overall survival in these patients. Thereafter, up to seven large, randomized phase III clinical trials investigating other molecular therapies in the first-line and second-line settings have failed to improve on the results observed with this agent. Potential reasons for this include intertumour heterogeneity, issues with trial design and a lack of predictive biomarkers of response. During the past 5 years, substantial advances in our knowledge of the human genome have provided a comprehensive picture of commonly mutated genes in patients with HCC. This knowledge has not yet influenced clinical decision-making or current clinical practice guidelines. In this Review the authors summarize the molecular concepts of progression, discuss the potential reasons for clinical trial failure and propose new concepts of drug development, which might lead to clinical implementation of emerging targeted agents.
Little is known about the mutational landscape of advanced hepatocellular carcinoma (HCC), and predictive biomarkers of response to systemic therapies are lacking. We aimed to describe the mutational ...landscape of advanced HCC and to identify predictors of primary resistance to systemic therapies using circulating tumor DNA (ctDNA). We prospectively enrolled 121 patients between October 2015 and January 2019. We performed targeted ultra-deep sequencing of 25 genes and Digital Droplet PCR of TERT promoter, including sequential samples throughout treatment. Primary endpoint was progression-free survival (PFS) stratified by mutation profiles in ctDNA. Secondary endpoints were overall survival and objective response rate. The most frequent mutations in ctDNA of advanced HCC were TERT promoter (51%), TP53 (32%), CTNNB1 (17%), PTEN (8%), AXIN1, ARID2, KMT2D, and TSC2 (each 6%). TP53 and CTNNB1 mutations were mutually exclusive. Patients with mutations in the PI3K/MTOR pathway had significantly shorter PFS than those without these mutations after tyrosine kinase inhibitors (2.1 vs 3.7 months, p < 0.001), but not after immune checkpoint inhibition (CPI). WNT pathway mutations were not associated with PFS, overall survival, or objective response after CPI. Serial profiling of ctDNA in a subset correlated with treatment response. Mutation profiling of ctDNA in advanced HCC shows similar mutation frequencies for known HCC drivers compared to early stages and identifies predictive biomarkers of response to systemic therapies.
The management of hepatocellular carcinoma (HCC) has substantially changed in the past few decades. Improvements in patient stratification (for example, using the Barcelona Clinic Liver Cancer ...staging system) and the introduction of novel therapies (such as sorafenib) have improved patient survival. Nevertheless, HCC remains the third most common cause of cancer-related deaths worldwide. Decision-making largely relies on evidence-based criteria, as depicted in the US and European clinical practice guidelines, which endorse five therapeutic recommendations: resection; transplantation; radiofrequency ablation; chemoembolization; and sorafenib. However, areas still exist in which uncertainty precludes a strong recommendation, such as the role of adjuvant therapies after resection, radioembolization with yttrium-90 or second-line therapies for advanced HCC. Many clinical trials that are currently ongoing aim to answer these questions. The first reported studies, however, failed to identify novel therapeutic alternatives (that is, sunitinib, erlotinib or brivanib). Moreover, genomic profiling has enabled patient classification on the basis of molecular parameters, and has facilitated the development of new effective drugs. However, no oncogene addiction loops have been identified so far, as has been the case with other cancers such as melanoma, lung or breast cancer. Efforts that focus on the implementation of personalized medicine approaches in HCC will probably dominate research in the next decade.
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